The Multifaceted Roles of Adipose Tissue-Therapeutic Targets for Diabetes and Beyond: The 2015 Banting Lecture

Abstract

The Banting Medal for Scientific Achievement is the highest scientific award of the American Diabetes Association (ADA). Given in memory of Sir Frederick Banting, one of the key investigators in the discovery of insulin, the Banting Medal is awarded annually for scientific excellence, recognizing significant long-term contributions to the understanding, treatment, or prevention of diabetes. Philipp E. Scherer, PhD, of the Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, received the prestigious award at the ADA's 75th Scientific Sessions, 5-9 June 2015, in Boston, MA. He presented the Banting Lecture, "The Multifaceted Roles of Adipose Tissue-Therapeutic Targets for Diabetes and Beyond," on Sunday, 7 June 2015.A number of different cell types contribute to the cellular architecture of adipose tissue. Although the adipocyte is functionally making important contributions to systemic metabolic homeostatis, several additional cell types contribute a supportive role to bestow maximal flexibility on the tissue with respect to many biosynthetic and catabolic processes, depending on the metabolic state. These cells include vascular endothelial cells, a host of immune cells, and adipocyte precursor cells and fibroblasts. Combined, these cell types give rise to a tissue with remarkable flexibility with respect to expansion and contraction, while optimizing the ability of the tissue to act as an endocrine organ through the release of many protein factors, critically influencing systemic lipid homeostasis and biochemically contributing many metabolites. Using an example from each of these categories-adiponectin as a key adipokine, sphingolipids as critical mediators of insulin sensitivity, and uridine as an important metabolite contributed by the adipocyte to the systemic pool-I will discuss the emerging genesis of the adipocyte over the past 20 years from metabolic bystander to key driver of metabolic flexibility.

Figure 1

The role of inflammation in the adipocyte. Genetic approaches to suppress local inflammatory responses in the adipocyte include a dominant-negative (dn) TNFα ligand that unproductively engages the TNF receptors, a potent adenoviral anti-inflammatory molecule called RID, and a traditional “super-repressor” of inflammation in the form of a mutant IκBα.

Figure 2

The consequences of a suppressed inflammatory response of the adipocyte. The process of adipose tissue expansion requires an inflammatory response as part of the healthy expansion process. By inhibiting these inflammatory events, adipogenesis is impaired, thereby reducing the number of fat cells available to accommodate any excess lipids, leading to ectopic lipid deposition in the liver. This also leads to a compromised intestinal barrier and the enhanced release of endotoxin into the system. Therefore, despite an early anti-inflammatory action at the level of the adipocyte, chronic systemic inflammation and severe systemic insulin resistance ensue in this setting.

Figure 3

The different types of adipocytes. Distinct precursor cells give rise to the different types of adipocytes, the classic white and brown adipocytes and the beige adipocytes that may transition to a “dormant” cell resembling a white adipocyte when their presence is not required. All these events require extensive remodeling of the extracellular matrix microenvironment of these cells.

Figure 4

The adipocyte as a professional secretory cell. Many distinct categories of secretory proteins have been reported to be released from adipocytes. Acrp30, adipocyte complement-related protein of 30 kDa; ASP, acylation-stimulating protein; ECM, extracellular matrix; IL-6, interleukin 6; MT1-MMP, membrane type 1 matrix metalloproteinase; PTX-3, pentraxin 3; RBP4, retinol-binding protein 4.